Drug Delivery
The worldwide transdermal patch market for the delivery of drug substances into or through the skin approaches $4 billion, yet is based on only a small number of drugs. The limitations on the number of drugs which are routinely administered transdermally is largely a consequence of the outermost 10-15 μm (in the dry state) of tissue, the stratum corneum (SC). The SC thus constitutes the main barrier to exogenous substances, including drugs. Before being taken up by blood vessels in the upper dermis and prior to entering the systemic circulation, substances permeating the skin must diffuse through the highly organised intercellular lipid bilayers of the SC. This intercellular microroute, which is lipophilic, is the primary pathway for exogenous substances to pass through the SC barrier by passive diffusion along a concentration gradient between delivery vehicle and the SC. The ideal properties of a molecule capable of effective passive diffusion and, thus, penetration through the SC barrier are known to be:                1. Molecular mass less than 600 Da        2. Adequate solubility in both oil and water so that the membrane concentration gradient, which is the driving force for passive drug diffusion along a concentration gradient, may be high        3. Partition coefficient such that the drug can diffuse out of the vehicle, partition into, and move across the SC, without becoming sequestered within it        4. Low melting point, correlating with good solubility, as predicted by ideal solubility theory.        
Drug molecules that suffer poor oral bioavailability or susceptibility to first-pass metabolism, and are thus often ideal candidates for transdermal delivery, often fail to realise their clinical application because they do not meet one or more of the above conditions. Macromolecular drugs such as peptides, proteins and nucleic acid fragments are precluded from successful transdermal administration, not only by their large sizes, but also by their extreme hydrophilicities. Drugs with substantial aqueous solubilities, for example, water-soluble salts of drug substances with acidic or basic moieties, are precluded from successful transdermal administration by their inability to cross the lipophilic intercellular microroute through the SC barrier.
Several approaches have been used to enhance the transport of drugs through the SC. However, in many cases, only moderate success has been achieved and each approach is associated with significant problems.
Chemical penetration enhancers allow only a modest improvement in penetration. Chemical modification of the penetrant to increase lipophilicity is not always possible and, in any case, necessitates additional studies for regulatory approval, due to generation of new chemical entities. Significant enhancement in delivery of a large number of drugs has been reported using iontophoresis. However, specialized devices are required and the agents delivered tend to accumulate in the skin appendages. The method is presently best-suited to acute applications. Electroporation and sonophoresis are known to increase transdermal delivery. However, they may both cause pain and local skin reactions and sonophoresis may cause breakdown of the therapeutic entity. Techniques aimed at removing the SC barrier, such as tape-stripping and suction/laser/thermal ablation are impractical, while needle-free injections have so far failed to replace conventional needle-based delivery, for example of insulin. Clearly, a robust alternative strategy is required to enhance drug transport across the SC and thus widen the range of drug substances amenable to transdermal delivery.
Minimally Invasive Monitoring
Minimally-invasive monitoring, whereby blood concentrations of drugs and analytes, such as glucose and drug substances, can be indirectly assessed without recourse to direct blood sampling, produces less pain, inconvenience and risk of infection for patients and saves clinician and nursing time. However, the stratum corneum has evolved into an exquisite, almost impermeable, barrier to outward migration of blood constituents. The small amounts of sweat and sebum produced under normal conditions mean that their collection and analysis is not practical. In any case, their composition does not, in most instances, accurately reflect blood concentration of analytes of interest. In minimally-invasive monitoring, interstitial fluid in the skin is extracted and used to accurately estimate blood analyte concentrations. The technique is fraught with difficulties, though, and often requires very specialized equipment. Given that sales of conventional finger-prick analysis devices for direct monitoring of blood glucose alone total $2 billion per annum, advancements in this field would be clinically desirable.
The concept of using a microstructured device consisting of a plurality of microprotrusions to breach the stratum corneum barrier was first proposed in the 1970s. Various devices comprising solid microprotrusions have been developed to produce a system that will puncture the stratum corneum leaving microscopic holes and that will enable subsequent inward drug delivery or outward migration of interstitial fluid. The production of solid microprotrusions and microneedle arrays using for example silicon have been described in the art, for example see U.S. Pat. Nos. 6,743,211, 6,743,211, 6,743,211, IE 2005/0825, U.S. Pat. Nos. 60/749,086, 6,924,087, 6,743,211, 6,663,820, 6,743,211, 6,767,341, 6,743,211, 6,663,820, 6,652,478, 6,743,211, 6,749,792, 6,451,240, 6,767,341, 6,743,211, 6,230,051, 6,908,453, 7,108,681, 6,931,277, EP1517722B1,US20060200069A1, U.S. Pat. Nos. 6,611,707, 6,565,532, 6,960,193, 6,743,211, 6,379,324, WO2007/040938A1, U.S. Pat. Nos. 6,256,533, 6,743,211, 6,591,124, 7,027,478, 6,603,987, 6,821,281, and 6,565,532.
A method for preparing solid microprotrusions from dextrin, chondroitin and albumin has been disclosed by Kyoto Pharmaceutical University (Ito et al, J Drug Target 14 (5): 255-261 2006; Ito et al, Eur J Pharm Sci 29: 82-88 2006). This “thread forming” method involves spreading a solution containing a known “thread-forming” material on a flat surface. The solution then has its surface contacted by a projection, which is moved upwards quickly, forming a series of polymer “threads”, which then dry to form microprotrusions. However, microprotrusions prepared from molten carbohydrate materials (eg dextrin, maltose) are extremely hygroscopic and rapidly absorb moisture under ambient conditions, losing their shape and becoming soft and extremely adhesive. Carbohydrate-based microprojections, upon skin puncture, rapidly form an adhesive matrix that blocks the formed holes, preventing appreciable drug delivery. Furthermore, drug loss is associated with such microprotrusion manufacture, as the drug substance needs to be heated to high temperatures required to melt such carbohydrate materials.
However, despite the considerable published work in the area of microprotrusions, it is particularly noteworthy that no microprotrusion-based products are presently marketed for the delivery of beneficial substances into or through the skin, or for the monitoring of levels of substances of diagnostic interest in the body. This is because the use of such systems presently known in the art is associated with a number of significant problems for these purposes, namely:    1 Production of microprotrusions by most previously patented methods is expensive;    2 Elemental silicon, widely used as the material for microprotrusions, is not an FDA-approved biomaterial & broken silicon or metal microprotrusions could cause skin problems—This is a particular problem for the notoriously brittle microprojections produced by dry etching of silicon;    3 Solid, non-coated needles require a two-step application process, which is undesirable;    4 Accurately coating microprotrusions is difficult and these coated microprotrusions subsequently only deliver a very small amount of drug as a bolus;    5 Preliminary experiments, conducted in our laboratory using human volunteers (n=5), showed transepidermal water loss (TEWL), a measure used worldwide as an indication of stratum corneum permeability, increased to approximately 30 g m−2 h−1 immediately upon microprotrusion puncture, but had returned to background (10 g m−2 h−1) within about 5 minutes;    6 Hollow microprotrusions have only one outlet and can become blocked by compressed dermal tissue;    7 Biomolecules can be significantly degraded by the heating used to produce polymeric microprotrusions from molten polymers or carbohydrates; and    8 The strength of carbohydrate and polymeric microprotrusions may be significantly compromised by incorporation of drug substances.
Thus the use of conventional microprotrusion based devices is associated with a great number of problems.